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Senescent-like Microglia Limit Remyelination Through the Senescence Associated Secretory Phenotype
Gross et al., Nature Communications. 2025.
https://www.nature.com/articles/s41467-025-57632-w
Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease in which immune cells infiltrate the central nervous system and promote deterioration of myelin and neurodegeneration. The capacity to regenerate myelin in the central nervous system diminishes with age. In this study, researchers used 2- to 3-month-old (young), 12-month-old (middle-aged), and 18- to 22-month-old (aged) C57BL/6 male and female mice. Results showed an upregulation of the senescence marker P16ink4a (P16) in microglial and macrophage cells within demyelinated lesions. Notably, treatment of senescent cells using genetic and pharmacological senolytic methods leads to enhanced remyelination in young and middle-aged mice but fails to improve remyelination in aged mice. These results suggest that therapeutic targeting of senescence-associated secretory phenotype components may improve remyelination in aging and MS. Supported by ORIP (R24OD036199), NIA, NINDS, and NIMH.
Suppressing APOE4-Induced Neural Pathologies by Targeting the VHL-HIF Axis
Jiang et al., PNAS. 2025.
https://pubmed.ncbi.nlm.nih.gov/39874294
The ε4 variant of human apolipoprotein E (APOE4) is a major genetic risk factor for Alzheimer’s disease and increases mortality and neurodegeneration. Using Caenorhabditis elegans and male APOE-expressing mice, researchers determined that the Von Hippel-Lindau 1 (VHL-1) protein is a key modulator of APOE4-induced neural pathologies. This study demonstrated protective effects of the VHL-1 protein; the loss of this protein reduced APOE4-associated neuronal and behavioral damage by stabilizing hypoxia-inducible factor 1 (HIF-1), a transcription factor that protects against cellular stress and injury. Genetic VHL-1 inhibition also mitigated cerebral vascular injury and synaptic damage in APOE4-expressing mice. These findings suggest that targeting the VHL–HIF axis in nonproliferative tissues could reduce APOE4-driven mortality and neurodegeneration. Supported by ORIP (R24OD010943, R21OD032463, P40OD010440), NHGRI, NIA, and NIGMS.
Functional Differences Between Rodent and Human PD-1 Linked to Evolutionary Divergence
Masubuchi et al., Science Immunology. 2025.
https://pubmed.ncbi.nlm.nih.gov/39752535/
Programmed cell death protein 1 (PD-1), an immune checkpoint receptor, regulates immunity against cancer. Rodent models (e.g., mice) do not exhibit the same response rates and immune-related adverse effects to PD-1 blocking drugs as patients with cancer. Only 59.6% amino acid sequence identity is conserved in human PD-1 (hu PD-1) and mouse PD-1 (mo PD-1). Researchers used mouse tumor models, coculture assays, and biophysical assays to determine key functional and biochemical differences between hu PD-1 and mo PD-1. HuPD-1 demonstrates stronger suppressive activity of interleukin-2 secretion and CD69 expression than mo PD-1 because of the ectodomain and intracellular domain, but not the transmembrane domain. Analysis of rodent evolution demonstrated that other inhibitory immunoreceptors were positively selected or had selection intensification over PD-1. Understanding the conservation and divergence of PD-1 signaling at the molecular level in humans compared with mice is needed to properly translate preclinical data to clinical therapeutics. Supported by ORIP (S10OD026929), NCI, and NIA.
Mechanical Force of Uterine Occupation Enables Large Vesicle Extrusion From Proteostressed Maternal Neurons
Wang et al., eLife. 2024.
https://pubmed.ncbi.nlm.nih.gov/39255003
This study investigates how mechanical forces from uterine occupation influence large vesicle extrusion (exopher production) from proteostressed maternal neurons in Caenorhabditis elegans. Exophers, previously found to remove damaged cellular components, are poorly understood. Researchers demonstrate that mechanical stress significantly increases exopher release from touch receptor neurons (i.e., ALMR) during peak reproductive periods, coinciding with egg production. Genetic disruptions reducing reproductive activity suppress exopher extrusion, whereas interventions promoting egg retention enhance it. These findings reveal that reproductive and mechanical factors modulate neuronal stress responses, providing insight on how systemic physiological changes affect neuronal health and proteostasis, with broader implications for reproductive-neuronal interactions. Supported by ORIP (R24OD010943, P40OD010440), NIA, and NIGMS.
Impaired Skeletal Development by Disruption of Presenilin-1 in Pigs and Generation of Novel Pig Models for Alzheimer's Disease
Uh et al., Journal of Alzheimer's Disease. 2024.
https://pubmed.ncbi.nlm.nih.gov/39177593/
This study explored the effects of presenilin 1 (PSEN1) disruption on vertebral malformations in male and female PSEN1 mutant pigs. Researchers observed significant skeletal impairments and early deaths in pigs with a PSEN1 null mutation, mirroring phenotypes seen in mouse models of Alzheimer’s disease (AD). This porcine model provides valuable insights into pathological hallmarks of PSEN1 mutations in AD, offering a robust platform of therapeutic exploration. The findings establish pigs as an essential translational model for AD, enabling advanced studies on pathophysiology and treatment development for human skeletal and neurological conditions. Supported by ORIP (U42OD011140), NHLBI, NIA, NIAID.
Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy
Racine et al., Journal of Immunology. 2024.
Myocarditis has emerged as a relatively rare but often lethal autoimmune complication of checkpoint inhibitor (ICI) cancer therapy, and significant mortality is associated with this phenomenon. Investigators developed a new mouse model system that spontaneously develops myocarditis. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, the treatment accelerates skeletal muscle myositis. The team performed characterization of cardiac and skeletal muscle T cells using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies. Supported by ORIP (U54OD020351, U54OD030187), NCI, NIA, NIDDK, and NIGMS.
Effect of Hormone Replacement Therapy on Amyloid Beta (Aβ) Plaque Density in the Rhesus Macaque Amygdala
Appleman et al., Frontiers in Aging Neuroscience. 2024.
https://www.frontiersin.org/articles/10.3389/fnagi.2023.1326747/full
Amyloid beta plaque density is associated with Alzheimer’s disease. In this study, the authors examined its concentration in aged female nonhuman primates’ cerebrospinal fluid, as well as in the amygdala, an area of the brain involved with emotion and memory. They set out to test the hypothesis that estrogen hormone replacement therapy can beneficially affect amygdala Aβ plaque density in “surgically menopausal” females (i.e., aged rhesus macaques that had undergone ovariectomy). Female rhesus macaques that received estrogen replacement therapy showed fewer amyloid plaques than those that did not receive the hormone. This effect was observed regardless of the type of diet that the animals consumed. These findings suggest that hormone replacement might be a helpful treatment to consider for Alzheimer’s disease. Supported by ORIP (P51OD011092, R24OD011895, S10OD025002) and NIA.
Deep Analysis of CD4 T Cells in the Rhesus CNS During SIV Infection
Elizaldi et al., PLOS Pathogens. 2023.
https://pubmed.ncbi.nlm.nih.gov/38060615/
Systemic HIV infection results in chronic inflammation that causes lasting damage to the central nervous system (CNS), despite long-term antiretroviral therapy (ART). Researchers studied neurocognitive outcomes in male and female rhesus macaques infected with simian immunodeficiency virus (SIV) using an ART regimen simulating suboptimal adherence; one group received no ART, and the other received ART with periodic interruptions. Using single-cell transcriptomic profiling, the researchers also identified molecular programs induced in the brain upon infection. They found that acute infection led to marked imbalance in the CNS CD4/CD8 T‑cell ratio, which persisted into the chronic phase. The studies provide insight into the role of CD4 T cells in the CNS during HIV infection. Supported by ORIP (P51OD011107, K01OD023034), NIA, NIAID, and NCI.
SALL1 Enforces Microglia-Specific DNA Binding and Function of SMADs to Establish Microglia Identity
Fixsen et al., Nature Immunology. 2023.
https://doi.org/10.1038/s41590-023-01528-8
Microglia function is thought to play a role in neurodevelopmental, psychiatric, and neurodegenerative diseases. Using knockout mice, investigators explored functional interactions between spalt-like transcription factor 1 (SALL1) and SMAD4, which demonstrated that interactions are mediated by a conserved microglia-specific SALL1 super-enhancer and result in direct activation of regulatory elements. The concerted interactions induce a microglia lineage determining program of gene expression. These findings indicate that expression of SALL1 and associated genes could contribute to phenotypes of aging and neurodegenerative diseases. Supported by ORIP (S10OD026929), NIA, NIMH, and NINDS.
p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy
Faget et al., Cancer Discovery. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238649/
This study emphasizes the importance of the metastatic tumor microenvironment in metastatic breast cancer growth and the identification of effective antimetastatic therapies. Using a stromal labeling approach and single-cell RNA sequencing, the authors showed that a combination of p38MAPK inhibition (p38i) and anti-OX40 synergistically reduced metastatic tumor growth and increased overall survival. Further engagement of cytotoxic T cells cured all metastatic disease in mice and produced durable immunologic memory. The Cancer Genome Atlas data analysis revealed that patients with p38i metastatic stromal signature and a high tumor mutational burden (TMB) had increased overall survival. These findings suggest that patients with high TMB would benefit the most from the p38i plus anti-OX40 approach. Supported by ORIP (S10OD028483), NIA, NCI, and NIGMS.